Single psilocybin dose reduced depression, functional disability over 6 weeks

Key takeaways:

• One psilocybin dose reduced depression and functional disability symptoms over 6 weeks vs. placebo.
• Psilocybin could benefit those not responding to other treatments or wary of long-term treatment.

A single dose of psilocybin resulted in clinically and statistically significant reductions in depressive symptoms and functional disability compared with placebo in patients with major depressive disorder, according to a phase 2 study.

The study, published in JAMA, found that 6 weeks after receiving 25 mg of synthetic psilocybin, those patients scored lower on the Montgomery-Åsberg Depression Rating Scale (MADRS) than a niacin-based placebo group by a mean of 12.3 points (95% CI, –17.5 to –7.2).

Psilocybin-treated patients also experienced less impairment to their social, family and work/school responsibilities. At 43 days, their mean change in Sheehan Disability Scale score was –4.07 (95% CI, –4.88 to –3.26) vs. the niacin group’s change of –1.76 (95% CI, –2.62 to –0.91).

The study was led by the nonprofit Usona Institute, which is investigating psilocybin for treatment of major depressive disorder. The “truly encouraging” results could “provide hope” for those who have not responded to other treatments or wish to avoid long-term antidepressant treatment, lead investigator Charles L. Raison, MD, said in a statement issued by Usona Institute.

The study, conducted at 11 U.S. sites between December 2019 and June 2022, enrolled 104 adults aged 21 to 65 years meeting DSM-5 criteria for an ongoing depressive episode of at least 60 days. They were randomly assigned to receive either 25 mg of psilocybin (n = 51) or 100 mg of niacin (n = 53), as well as two facilitators to help each participant through preparatory sessions, the dosing session and 4 hours of post-dose discussions.

At day 8, the psilocybin group’s mean MADRS score change was –17.8 (95% CI, –21.1 to –14.6) compared with the niacin group’s change of –5.8 (95% CI, –9.1 to –2.6). At day 43, the psilocybin group’s mean change widened to –19.1 (95% CI, –22.7 to –15.5), while the niacin group’s change was –6.8 (95% CI, –10.5 to –3.1).

Psilocybin was associated with more overall adverse events than placebo (44 vs. 33), but adverse events were mostly mild to moderate and resolved within the dosing period.

There were no serious treatment-emergent adverse events, researchers wrote, while finding a “reasonable possibility” that severe adverse events in four psilocybin-treated patients were drug-related. Researchers added that those adverse events — migraine, headache, illusion, panic attack and paranoia — were known effects of psilocybin.

After the acute effects of psilocybin resolved, 44% of participants (n = 22) reported visual perceptual effects on the day of dosing. After the dosing day, 6% (n = 3) reported visual effects, and no visual effects were reported from day 10 until the end of the study.

Though psilocybin showed benefit, the trial was “relatively small,” Rachel Yehuda, PhD, and Amy Lehrner, PhD, wrote in a related editorial published in JAMA. Future studies will clarify who is most likely to benefit, whether booster or repeated treatment is warranted and what the optimal dose and therapeutic frameworks are, they wrote.

References:

• Usona statement on JAMA publication of PSIL201 data. https://www.usonainstitute.org/updates/usona-statement-on-jama-publication-of-psil201-data. Published Aug. 31, 2023. Accessed Sept. 6, 2023.
• Yehuda R, et al. JAMA. 2023;doi:10.1001/jama.2023.12900.